Chronic kidney disease (CKD), defined as a persistently reduced glomerular filtration rate (GFR), is an important public health problem affecting more than 26 million Americans. Cardiovascular diseases are the leading cause of morbidity and mortality in the United States and the presence of CKD is now recognized as an independent risk predictor for cardiovascular events. CKD leads to metabolic disturbances that amplify the risks of cardiovascular disease and premature death independent of diabetes mellitus, hypertension, or other traditional cardiovascular risk factors exemplified in the Framingham Study. Treatments that have proven effective in reducing cardiovascular morbidity and mortality in the general population have been less successful in patients with CKD, and the evidence basis from controlled interventional studies to support therapies for lowering cardiovascular risk in the CKD population have been woefully inadequate to date. When progression of CKD to end-stage renal disease (ESRD) cannot be prevented, then either dialysis or kidney transplantation are required to prevent immediate mortality. Unfortunately, over the past 20 years, there has been no successful implementation of a new therapeutic agent specifically designed to slow the progression of CKD to ESRD, other than the use of inhibitors of the renin-angiotensin system. Lifestyle factors are root causes of CKD development, progression, and associated complications, yet have received scant attention in translational research. Data accumulated during the initial funding period demonstrated that central obesity and associated adiposity independently and additively influence the degree of oxidative stress, inflammation, and insulin resistance while additional new preliminary data demonstrates that levels of physical activity are closely associated with kidney disease progression. These findings suggest that interventions targeting caloric excess, reduced physical activity, and resulting adiposity may be beneficial in slowing kidney disease progression and reducing cardiovascular risk in patients with CKD by influencing oxidative stress pathways. In experimental models and available human studies, healthy lifestyle interventions, such as aerobic exercise and dietary caloric restriction, have demonstrated antioxidant effects mediated via induction of mitochondrial biogenesis, induction of antioxidant enzymes, and reduction of free radical mitochondrial leak during oxidative phosphorylation. The central aim of this proposal is to improve understanding of how metabolic pathways that contribute to adiposity also amplify risks of kidney disease progression and cardiovascular disease in subjects with moderate to severe CKD. We hypothesize that higher levels of physical activity, and healthy dietary characteristics (greater polyunsaturated to saturated fat ratio, lower glycemic index, lower processed food intake) will be associated with lower risks of CKD progression, and major atherosclerotic cardiovascular events. We further hypothesize that implementation of caloric restriction and aerobic exercise is feasible and can improve the metabolic milieu. PUBLIC HEALTH RELEVANCE: CKD is an important risk amplifier for cardiovascular disease, mediated through increased oxidative stress, inflammation, and insulin resistance. Lifestyle factors are root causes of CKD development, progression, and associated complications, yet have received scant attention in translational research. The central aim of this proposal is to improve understanding of how metabolic pathways that contribute to adiposity also amplify risks of kidney disease progression and cardiovascular disease in subjects with moderate to severe CKD.